CN1655776A - 泻药组合物 - Google Patents
泻药组合物 Download PDFInfo
- Publication number
- CN1655776A CN1655776A CNA018183239A CN01818323A CN1655776A CN 1655776 A CN1655776 A CN 1655776A CN A018183239 A CNA018183239 A CN A018183239A CN 01818323 A CN01818323 A CN 01818323A CN 1655776 A CN1655776 A CN 1655776A
- Authority
- CN
- China
- Prior art keywords
- atom
- compositions
- formula
- carbon
- purposes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 77
- 206010010774 Constipation Diseases 0.000 title claims abstract description 28
- 230000000694 effects Effects 0.000 claims abstract description 17
- 125000001153 fluoro group Chemical group F* 0.000 claims abstract description 15
- -1 dicyclic compound Chemical class 0.000 claims description 54
- 150000001875 compounds Chemical class 0.000 claims description 50
- 229910052799 carbon Inorganic materials 0.000 claims description 39
- 230000000968 intestinal effect Effects 0.000 claims description 32
- 125000000217 alkyl group Chemical group 0.000 claims description 24
- 238000000034 method Methods 0.000 claims description 24
- 238000002360 preparation method Methods 0.000 claims description 22
- 150000001721 carbon Chemical group 0.000 claims description 21
- 229910052736 halogen Inorganic materials 0.000 claims description 20
- 150000002367 halogens Chemical class 0.000 claims description 20
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 19
- 125000003118 aryl group Chemical group 0.000 claims description 18
- 229910052760 oxygen Inorganic materials 0.000 claims description 15
- 239000001301 oxygen Substances 0.000 claims description 14
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- 239000001257 hydrogen Substances 0.000 claims description 13
- 229910052739 hydrogen Inorganic materials 0.000 claims description 13
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 13
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 12
- 229920006395 saturated elastomer Polymers 0.000 claims description 12
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 11
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 11
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 10
- 125000004104 aryloxy group Chemical group 0.000 claims description 9
- 125000000000 cycloalkoxy group Chemical group 0.000 claims description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 8
- 239000004215 Carbon black (E152) Substances 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 8
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 8
- 230000035568 catharsis Effects 0.000 claims description 8
- 125000000623 heterocyclic group Chemical group 0.000 claims description 8
- 125000004043 oxo group Chemical group O=* 0.000 claims description 8
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 claims description 8
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 7
- 239000000194 fatty acid Substances 0.000 claims description 7
- 229930195729 fatty acid Natural products 0.000 claims description 7
- 150000004665 fatty acids Chemical class 0.000 claims description 7
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 6
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000004423 acyloxy group Chemical group 0.000 claims description 5
- 125000003545 alkoxy group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 5
- 241001597008 Nomeidae Species 0.000 claims description 4
- 125000000524 functional group Chemical group 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- 229910052757 nitrogen Inorganic materials 0.000 claims description 4
- LADGBHLMCUINGV-UHFFFAOYSA-N tricaprin Chemical compound CCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCC)COC(=O)CCCCCCCCC LADGBHLMCUINGV-UHFFFAOYSA-N 0.000 claims description 4
- 229940093633 tricaprin Drugs 0.000 claims description 4
- 150000002431 hydrogen Chemical class 0.000 claims 3
- 150000002576 ketones Chemical class 0.000 claims 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims 3
- 238000004140 cleaning Methods 0.000 claims 1
- 206010000087 Abdominal pain upper Diseases 0.000 abstract description 4
- 125000002950 monocyclic group Chemical group 0.000 abstract description 3
- 239000004480 active ingredient Substances 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 27
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 26
- 239000002253 acid Substances 0.000 description 24
- 239000000243 solution Substances 0.000 description 19
- 238000012360 testing method Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 17
- 150000002148 esters Chemical class 0.000 description 13
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 12
- 239000007788 liquid Substances 0.000 description 11
- 239000003921 oil Substances 0.000 description 11
- 235000019198 oils Nutrition 0.000 description 11
- 229920000858 Cyclodextrin Polymers 0.000 description 10
- 239000002585 base Substances 0.000 description 9
- 125000005843 halogen group Chemical group 0.000 description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 8
- 206010012735 Diarrhoea Diseases 0.000 description 8
- 229940125904 compound 1 Drugs 0.000 description 8
- 125000000468 ketone group Chemical group 0.000 description 8
- 150000003180 prostaglandins Chemical class 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 125000001424 substituent group Chemical group 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 229940125782 compound 2 Drugs 0.000 description 6
- 239000012043 crude product Substances 0.000 description 6
- 210000003736 gastrointestinal content Anatomy 0.000 description 6
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 6
- 238000010898 silica gel chromatography Methods 0.000 description 6
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid Chemical compound CCCCCCCCCCCC(O)=O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 5
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 5
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 238000010521 absorption reaction Methods 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 description 4
- 230000033001 locomotion Effects 0.000 description 4
- 150000004671 saturated fatty acids Chemical class 0.000 description 4
- 239000000741 silica gel Substances 0.000 description 4
- 229910002027 silica gel Inorganic materials 0.000 description 4
- 229960001866 silicon dioxide Drugs 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005303 weighing Methods 0.000 description 4
- TWJNQYPJQDRXPH-UHFFFAOYSA-N 2-cyanobenzohydrazide Chemical compound NNC(=O)C1=CC=CC=C1C#N TWJNQYPJQDRXPH-UHFFFAOYSA-N 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 3
- 229960000583 acetic acid Drugs 0.000 description 3
- 239000000654 additive Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000004071 biological effect Effects 0.000 description 3
- 239000002775 capsule Substances 0.000 description 3
- 239000003795 chemical substances by application Substances 0.000 description 3
- 239000003792 electrolyte Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 210000004347 intestinal mucosa Anatomy 0.000 description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 3
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical group N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- GAWIXWVDTYZWAW-UHFFFAOYSA-N C[CH]O Chemical group C[CH]O GAWIXWVDTYZWAW-UHFFFAOYSA-N 0.000 description 2
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 description 2
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 2
- 241000792859 Enema Species 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 239000005639 Lauric acid Substances 0.000 description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 2
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 description 2
- 235000021360 Myristic acid Nutrition 0.000 description 2
- TUNFSRHWOTWDNC-UHFFFAOYSA-N Myristic acid Natural products CCCCCCCCCCCCCC(O)=O TUNFSRHWOTWDNC-UHFFFAOYSA-N 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 125000001931 aliphatic group Chemical group 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 2
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical compound NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Chemical compound BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- RYYVLZVUVIJVGH-UHFFFAOYSA-N caffeine Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2C RYYVLZVUVIJVGH-UHFFFAOYSA-N 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 230000001186 cumulative effect Effects 0.000 description 2
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 description 2
- PAFZNILMFXTMIY-UHFFFAOYSA-N cyclohexylamine Chemical compound NC1CCCCC1 PAFZNILMFXTMIY-UHFFFAOYSA-N 0.000 description 2
- 125000001559 cyclopropyl group Chemical group [H]C1([H])C([H])([H])C1([H])* 0.000 description 2
- 238000003745 diagnosis Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 239000007920 enema Substances 0.000 description 2
- 229940095399 enema Drugs 0.000 description 2
- 239000007850 fluorescent dye Substances 0.000 description 2
- 238000001215 fluorescent labelling Methods 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 230000000977 initiatory effect Effects 0.000 description 2
- 238000010813 internal standard method Methods 0.000 description 2
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical compound C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 150000003214 pyranose derivatives Chemical class 0.000 description 2
- 235000003441 saturated fatty acids Nutrition 0.000 description 2
- 235000009518 sodium iodide Nutrition 0.000 description 2
- 229910001220 stainless steel Inorganic materials 0.000 description 2
- 239000010935 stainless steel Substances 0.000 description 2
- 239000012086 standard solution Substances 0.000 description 2
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000012085 test solution Substances 0.000 description 2
- 125000003944 tolyl group Chemical group 0.000 description 2
- 230000008359 toxicosis Effects 0.000 description 2
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 2
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 2
- 229930195735 unsaturated hydrocarbon Natural products 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N 1H-pyrrole Natural products C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 1
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 1
- NJBCRXCAPCODGX-UHFFFAOYSA-N 2-methyl-n-(2-methylpropyl)propan-1-amine Chemical compound CC(C)CNCC(C)C NJBCRXCAPCODGX-UHFFFAOYSA-N 0.000 description 1
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 1
- XVMSFILGAMDHEY-UHFFFAOYSA-N 6-(4-aminophenyl)sulfonylpyridin-3-amine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)C1=CC=C(N)C=N1 XVMSFILGAMDHEY-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 description 1
- KZBUYRJDOAKODT-UHFFFAOYSA-N Chlorine Chemical compound ClCl KZBUYRJDOAKODT-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010019909 Hernia Diseases 0.000 description 1
- 101150020741 Hpgds gene Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- LPHGQDQBBGAPDZ-UHFFFAOYSA-N Isocaffeine Natural products CN1C(=O)N(C)C(=O)C2=C1N(C)C=N2 LPHGQDQBBGAPDZ-UHFFFAOYSA-N 0.000 description 1
- 239000003810 Jones reagent Substances 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- OPKOKAMJFNKNAS-UHFFFAOYSA-N N-methylethanolamine Chemical compound CNCCO OPKOKAMJFNKNAS-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 1
- 208000015815 Rectal disease Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 1
- 206010000059 abdominal discomfort Diseases 0.000 description 1
- 239000011358 absorbing material Substances 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 125000000641 acridinyl group Chemical group C1(=CC=CC2=NC3=CC=CC=C3C=C12)* 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 125000003342 alkenyl group Chemical group 0.000 description 1
- 125000004183 alkoxy alkyl group Chemical group 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 229940043377 alpha-cyclodextrin Drugs 0.000 description 1
- WMGSQTMJHBYJMQ-UHFFFAOYSA-N aluminum;magnesium;silicate Chemical compound [Mg+2].[Al+3].[O-][Si]([O-])([O-])[O-] WMGSQTMJHBYJMQ-UHFFFAOYSA-N 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 150000003863 ammonium salts Chemical class 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000767 anti-ulcer Effects 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 229960003121 arginine Drugs 0.000 description 1
- 229910052786 argon Inorganic materials 0.000 description 1
- 239000012300 argon atmosphere Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 229910052788 barium Inorganic materials 0.000 description 1
- DSAJWYNOEDNPEQ-UHFFFAOYSA-N barium atom Chemical compound [Ba] DSAJWYNOEDNPEQ-UHFFFAOYSA-N 0.000 description 1
- 238000005284 basis set Methods 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- RWCCWEUUXYIKHB-UHFFFAOYSA-N benzophenone Chemical compound C=1C=CC=CC=1C(=O)C1=CC=CC=C1 RWCCWEUUXYIKHB-UHFFFAOYSA-N 0.000 description 1
- 239000012965 benzophenone Substances 0.000 description 1
- 125000001164 benzothiazolyl group Chemical group S1C(=NC2=C1C=CC=C2)* 0.000 description 1
- 125000004196 benzothienyl group Chemical group S1C(=CC2=C1C=CC=C2)* 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 description 1
- 229960004853 betadex Drugs 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229910052794 bromium Inorganic materials 0.000 description 1
- 150000007516 brønsted-lowry acids Chemical class 0.000 description 1
- 150000007528 brønsted-lowry bases Chemical class 0.000 description 1
- 229960001948 caffeine Drugs 0.000 description 1
- VJEONQKOZGKCAK-UHFFFAOYSA-N caffeine Natural products CN1C(=O)N(C)C(=O)C2=C1C=CN2C VJEONQKOZGKCAK-UHFFFAOYSA-N 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 239000004227 calcium gluconate Substances 0.000 description 1
- 229960004494 calcium gluconate Drugs 0.000 description 1
- 235000013927 calcium gluconate Nutrition 0.000 description 1
- NEEHYRZPVYRGPP-UHFFFAOYSA-L calcium;2,3,4,5,6-pentahydroxyhexanoate Chemical compound [Ca+2].OCC(O)C(O)C(O)C(O)C([O-])=O.OCC(O)C(O)C(O)C(O)C([O-])=O NEEHYRZPVYRGPP-UHFFFAOYSA-L 0.000 description 1
- 208000015606 cardiovascular system disease Diseases 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000002052 colonoscopy Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229940039231 contrast media Drugs 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 125000004122 cyclic group Chemical group 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical compound NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 230000013872 defecation Effects 0.000 description 1
- PGZIKUPSQINGKT-UHFFFAOYSA-N dialuminum;dioxido(oxo)silane Chemical compound [Al+3].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O.[O-][Si]([O-])=O PGZIKUPSQINGKT-UHFFFAOYSA-N 0.000 description 1
- 230000000741 diarrhetic effect Effects 0.000 description 1
- ZBCBWPMODOFKDW-UHFFFAOYSA-N diethanolamine Chemical compound OCCNCCO ZBCBWPMODOFKDW-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000001839 endoscopy Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 210000003608 fece Anatomy 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- JKFAIQOWCVVSKC-UHFFFAOYSA-N furazan Chemical compound C=1C=NON=1 JKFAIQOWCVVSKC-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 229940080345 gamma-cyclodextrin Drugs 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000005842 heteroatom Chemical group 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001183 hydrocarbyl group Chemical group 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 125000002632 imidazolidinyl group Chemical group 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 125000005956 isoquinolyl group Chemical group 0.000 description 1
- 125000001786 isothiazolyl group Chemical group 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229960003646 lysine Drugs 0.000 description 1
- 235000001055 magnesium Nutrition 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- QSHDDOUJBYECFT-UHFFFAOYSA-N mercury Chemical compound [Hg] QSHDDOUJBYECFT-UHFFFAOYSA-N 0.000 description 1
- 229910052753 mercury Inorganic materials 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 125000001624 naphthyl group Chemical group 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 125000004934 phenanthridinyl group Chemical group C1(=CC=CC2=NC=C3C=CC=CC3=C12)* 0.000 description 1
- 125000001484 phenothiazinyl group Chemical group C1(=CC=CC=2SC3=CC=CC=C3NC12)* 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 238000003822 preparative gas chromatography Methods 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- MFDFERRIHVXMIY-UHFFFAOYSA-N procaine Chemical compound CCN(CC)CCOC(=O)C1=CC=C(N)C=C1 MFDFERRIHVXMIY-UHFFFAOYSA-N 0.000 description 1
- 229960004919 procaine Drugs 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 235000010409 propane-1,2-diol alginate Nutrition 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- WGJJROVFWIXTPA-OALUTQOASA-N prostanoic acid Chemical compound CCCCCCCC[C@H]1CCC[C@@H]1CCCCCCC(O)=O WGJJROVFWIXTPA-OALUTQOASA-N 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 125000003072 pyrazolidinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000005412 pyrazyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 125000002294 quinazolinyl group Chemical group N1=C(N=CC2=CC=CC=C12)* 0.000 description 1
- 125000005493 quinolyl group Chemical group 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- JZWFDVDETGFGFC-UHFFFAOYSA-N salacetamide Chemical group CC(=O)NC(=O)C1=CC=CC=C1O JZWFDVDETGFGFC-UHFFFAOYSA-N 0.000 description 1
- 230000003248 secreting effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- CMXPERZAMAQXSF-UHFFFAOYSA-M sodium;1,4-bis(2-ethylhexoxy)-1,4-dioxobutane-2-sulfonate;1,8-dihydroxyanthracene-9,10-dione Chemical compound [Na+].O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=CC=C2O.CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC CMXPERZAMAQXSF-UHFFFAOYSA-M 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000003335 steric effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 150000005621 tetraalkylammonium salts Chemical class 0.000 description 1
- DZLFLBLQUQXARW-UHFFFAOYSA-N tetrabutylammonium Chemical compound CCCC[N+](CCCC)(CCCC)CCCC DZLFLBLQUQXARW-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- XQKBFQXWZCFNFF-UHFFFAOYSA-K triiodosamarium Chemical compound I[Sm](I)I XQKBFQXWZCFNFF-UHFFFAOYSA-K 0.000 description 1
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- 125000005023 xylyl group Chemical group 0.000 description 1
- QMBQEXOLIRBNPN-UHFFFAOYSA-L zirconocene dichloride Chemical compound [Cl-].[Cl-].[Zr+4].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 QMBQEXOLIRBNPN-UHFFFAOYSA-L 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4741—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having oxygen as a ring hetero atom, e.g. tubocuraran derivatives, noscapine, bicuculline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
- A61K31/559—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing hetero atoms other than oxygen
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/10—Laxatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/12—Antidiarrhoeals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
- C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pyrane Compounds (AREA)
Abstract
本发明的目的是提供含作为活性成分的、双环/单环结构之比至少为1∶1的卤代双环化合物的抗便秘组合物。所述卤代双环化合物由式(I)表示,其中X1和X2优选都为氟原子。所述组合物可用于治疗便秘而无强烈的副作用例如胃痛。
Description
技术领域
本发明涉及一种新的泻药组合物,它用于缓解或预防便秘病人的便秘,也用于洗肠。
发明背景
前列腺素(下文中称作PGs)是具有多种生理学活性的脂肪酸类的总称,它存在于人体和动物组织和器官中。PGs基本上含有下式的前列腺烷酸骨架:
而某些合成产物可含有经某种修饰的上述骨架。根据五-元环的结构和取代基,将PGs分成几种类型,
C系列前列腺素(PGCs);
D系列前列腺素(PGDs);
等等。而且,它们可分成含13,14-双键的PG1s;含5,6-和13,14-双键的PG2s;和含5,6-,13,14-和17,18-双键的PG3s。
PGs的表示如下。根据基本骨架对PGs中的组成α-链、ω-链和五-元环的碳原子编号如下:
即,在基本骨架中,对构分碳原子(constituent carbon atoms)这样编号,羧基中的碳原子为C-1,α-链含C-2至C-7,向环方向增加数字,五-元环含C-8至C-12,ω-链含C-13-C-20。当α-链碳原子较少时,随后的C-2碳原子编号应适当改变,当多于7时,命名所述化合物,前提是C-2位的碳有代替羧基(在C-1位)的取代基。当ω-链含较少碳原子时,应使碳原子编号相应地小于20,而当多于8时,在21位和其后的碳原子应被看作取代基。除非另有描述,构型可认为是根据上述基本骨架。
例如,PGD、PGE和PGF指在C-9和/或C-11位有羟基的化合物。本发明中,PGs也包括有代替C-9和/或C-11位羟基的其它基团的那些,它们被称为9-去羟基-9-取代的或11-去羟基-11-取代的化合物。
而且,PGs可包括异构体,例如双环互变异构体、光学异构体;几何异构体等。
已知PGs有多种药理和生理活性,例如,血管舒张、消炎、血小板聚集、刺激子宫肌肉、刺激肠道肌肉、抗溃疡作用等。发现PGEs或PGFs具有因肠刺激引起的强烈的肠收缩作用,而肠蓄积(enteropooling)作用弱。由于副作用例如肠收缩引起的胃痛,因此,不可能用PGEs或PGFs作为泻药。
另一方面,发现具有13,14-单键和C-15构成羰基的PGs和具有13,14-双键和C-15构成羰基的那些PGs存在于人体或动物代谢物中。已知这些13,14-二氢-15-酮基-前列腺素和15-酮基-前列腺素(下文中称作15-酮基-PGs)是经体内相应PGs的酶代谢自然产生的代谢物。已报道这些15-酮基-PGs几乎没有表现出PGs具有的多种生理学活性并且是药理学和生理学上的非活性代谢物[参见,Acta PhysiologicaScandinavica,66,p.509-(1966)]。
Ueno等的美国专利5,317032描述了前列腺素泻药,包括双环互变异构体的存在。然而,至今仍未知所述双环互变异构体作为抗便秘治疗和预防剂的明显活性。
发明公开
然而,当估计15-酮基-PGs类似物的药理活性时,本发明者发现用小剂量的被一个或多个卤原子取代的相关双环化合物,即,所述的双环互变异构体可缓解便秘。具体说来,可用小剂量的氟原子在C-16位的上述化合物缓解便秘。如需要,可用产生强导泻(cathartic)作用的大剂量,尽管本发明基本目的是要恢复正常数目的肠运动(每周3-7次)。
本发明的一个目的是要提供一种泻药组合物,它用于治疗便秘和洗肠,而不产生大量的副作用例如胃痛。
因此,本发明提供一种泻药组合物,它包括产生导泻有效量的由式(I)表示的双环化合物:
其中V1和V2为碳或氧;
W1在V1为碳和W2在V2为碳时为
R3和R4为氢或其中之一为OH;
X1和X2为氢、低级烷基或卤素,且至少其中之一为卤素;
Z为碳、氧、硫或氮;
R2为氢或烷基;
Y为饱和或不饱和C2-10烃链,它是未取代的或被氧代、卤素、烷基、羟基、芳基或杂环基取代;
A为-CH2OH、-COCH2OH、-COOH或它的官能团衍生物;和
R1为未被取代或被卤素、氧代、羟基、低级烷氧基、低级烷酰氧基、低级环烷基、低级环烷氧基、芳基、芳氧基、杂环基或杂环氧基取代的饱和或不饱和的、成直链或支链的低级烃;低级环烷基;低级环烷氧基;芳基、芳氧基、杂环基或杂环氧基;
C-13和C-14位间的键为双或单键,和
C-15有R、S的空间构型或其混合物。
本发明也提供式(I)化合物制备泻药组合物的用途。
本发明也提供一种向有此需要的患者提供导泻作用的方法,它包括用式(I)化合物给药。
当式(I)双环卤代化合物提供良好的导泻作用时,所述化合物不产生强烈的副作用例如由肠收缩引起的胃痛。因此,本发明组合物不仅可用来治疗慢性或间歇性便秘,还可在患有与例如疝或心血管系统疾病相关的便秘患者中治疗或预防便秘(如需要也可松弛肠道),以避免排便困难或患上直肠性疾病。而且,在药物或食物中毒的情况下,所述组合物可用于引起正常肠运动,以洗出肠内的有害物质。另外,本发明的双环卤代化合物可用作预防、诊断或外科手术前用于肠预处理的肠清洗剂。
发明详述
本发明提供一种含导泻有效量的式(I)双环化合物的泻药组合物。
泻药通过下示四种机理中的一种或数种结合起作用,从而增加粪便的水分并加速肠内容物的转运:
(i)所述药物的亲水性和渗透压令水和电解质可保持于肠道内,从而,肠内容物的体积增加间接导致其转运加快。
(ii)所述药物可作用于肠粘膜以减少电解质和水的正常吸收总量而提高水量,间接导致肠内容物的转运加快。
(iii)所述药物可作用于肠粘膜以增加电解质和水的正常分泌总量并增加水量,直接和/或间接导致肠内容物转运加快。
(iv)所述药物首先产生肠运动以加快传递,由于吸收水和电解质的时间的减少而间接导致水和电解质的纯吸收减少。
用于本发明的肠蓄积试验主要是要研究作用(ii)和/或(iii),其通过测定肠内容物的体积评估所述药物对肠内水量的作用。本发明的双环卤代化合物可表现出极强的肠蓄积作用。然而它们几乎不或轻微地引起肠收缩,这是对作用(iv)的评估指标之一。因此,认为本发明的式(I)双环卤代化合物主要通过肠粘膜直接或间接影响电解质和水从肠壁转移到血管和/或从血管进入肠,导致水吸收减少和/或导致通过肠的水分泌增加,提高肠内水容量并加快肠内容物的转运以缓解便秘。
在式(I)的定义中,术语“未饱和”打算包括至少一或多个双键和/或三键,所述键孤立地(isolatedly)、分别地或连续地出现于主链和/或支链碳原子间。两个连续位置间的不饱和键通过表示两个位置中的较小数来表示,而在两个末端位置间的不饱和键通过表示两者的位置来表示。优选的不饱和键是2位的双键和在5位的双键或三键。
术语“低级”打算包括有1-8个碳原子的基团,除非另有说明。
术语“卤素”包括氟、氯、溴或碘原子。特别优选的是氟原子。
术语“低级烷氧基”指低级烷基-O-的基团,其中低级烷基为含1-6个碳原子的直链或支链饱和烃基,包括,例如,甲基、乙基、丙基、异丙基、丁基、异丁基、叔-丁基、戊基和己基。
术语“羟基(低级)烷基”指被至少一个羟基例如羟甲基、1-羟乙基、2-羟乙基和1-甲基-1-羟乙基所取代的如上所述的低级烷基。
术语“低级烷酰氧基”指由式RCO-O-表示的基团,其中的RCO-是如上定义的低级烷基氧化生成的酰基,例如乙酰基。
术语“低级环烷基”指含三个或多个碳原子的上述低级烷基的环化形成的环基,包括,例如,环丙基、环丁基、环戊基和环己基。
术语“低级环烷氧基”指低级-环烷基-O-,其中的低级环烷基如上所述。
术语“芳基”可包括未取代或被取代的芳香族碳环基团(优选单环基团),例如,苯基、萘基、甲苯基和二甲苯基。取代基的实例有卤原子和卤代(低级)烷基,其中的卤原子和低级烷基如上定义。
术语“芳氧基”指由式Ar-O表示的基团,其中Ar为如上定义的芳基。
术语“杂环基”可包括5-14,优选5-10元单环基,它具有作为其任选被碳原子和1-4个,优选1-3个由1-2种选自氧原子、氮原子和硫原子的杂原子所取代的构成原子,和由最多可达3个环部分(其中至少之一为如上定义的单环基组成的缩合杂环基。所述杂环基的实例包括呋喃基、噻吩基、吡咯基、噁唑基、异噁唑基、噻唑基、异噻唑基、咪唑基、吡唑基、呋咱基、吡喃基、吡啶基、哒嗪基、嘧啶基、pyrazyl、2-吡咯啉基、吡咯烷基、2-咪唑啉基、咪唑烷基、2-吡唑啉基、吡唑烷基、哌啶子基、哌嗪基、吗啉代、吲哚基、苯并噻吩基、喹啉基、异喹啉基、嘌呤基、喹唑啉基、咔唑基、吖啶基、菲啶基、苯并咪唑基、苯并咪唑酮基、苯并噻唑基、吩噻嗪基。在该情况下的取代基的实例包括卤素和卤素取代的低级烷基,其中的卤原子和低级烷基如上所述。
术语“杂环-氧基”指式HcO-所表示的基团,其中Hc为上述杂环基。
用于本发明的双环-16-卤化合物可为盐或具有酯化羧基或醚化基的化合物。这些盐包括药学上可接受的盐例如,碱金属例如钠、钾的盐;碱土金属例如钙、镁的盐;药理学上可接受的铵盐例如氨、甲胺、二甲胺、环戊胺、环己胺、苄基胺、哌啶、乙二胺、单乙醇胺、二乙醇胺、三乙醇胺、单甲基单乙醇胺、trometamine、赖氨酸、普鲁卡因、咖啡因、精氨酸、四烷基铵盐等。可用常规方法,例如从相应的酸和碱或通过盐交换制备这些盐。
这类酯和醚包括,例如,含一个或多个不饱和键的直链或支链烷基酯和醚例如,甲基、乙基、丙基、丁基、异丙基、异丁基、叔丁基、戊基、2-乙基己基的酯和醚;有脂环基例如环丙基、环戊基或环己基的那些酯或醚;含一个芳基如苄基或苯基(其中的芳基可含一个或多个取代基)的那些酯或醚;低级链烯基例如乙炔基和丙炔基、羟基烷基或烷氧基烷基例如羟乙基、羟基异丙基、聚羟基乙基、聚羟基异丙基、甲氧基乙基、乙氧基乙基或甲氧基异丙基的酯或醚;任选取代的芳基例如苯基、甲苯基、叔丁基苯基、水杨基、3,4-二-甲氧基苯基和苯甲酰氨基苯基的酯或醚;烷基甲硅烷基例如三甲基甲硅烷基或三乙基甲硅烷基的酯或醚;或四羟基吡喃基的酯或醚。
优选的酯和醚包括,例如,直链或支链低级烷基例如甲基、乙基、丙基、正丁基、异丙基或叔丁基的酯和醚;苄基的酯和醚;或羟基烷基例如羟基乙基或羟基异丙基的酯和醚。
优选A为-COOH或其药学上可接受的盐或酯。
优选X1和X2都是卤原子,更优选为氟原子。
优选W1为=O。
优选W2为其中R3和R4皆为氢原子。
优选Z为氧原子。
优选Y为有6-8个碳原子的未取代的饱和或不饱和烃链。
优选R1为有4-8个碳原子的未取代的饱和或不饱和烃链。
R2优选为氢原子。
本发明的组合物可包括上述化合物的异构体。这类异构体的实例包括在C-15位有酮基、C-16位有卤素的单环互变异构体;光学异构体;几何异构体等。
互变异构体I
互变异构体II
如上所示的C-11位的氧原子和C-15位的酮基间的互变异构体对在具有13,14-单键和C-16位上有两个氟原子的化合物的情况下特别重要。
已发现在无水情况下,式(I)表示的化合物主要以双环化合物的形式存在。在含水介质中,认为例如在C-15位的酮基位上出现氢键,从而阻止了双环的形成。而且,认为C-16位上的卤原子促使双环形成。例如单环/双环结构可以1∶6、1∶10和4∶96的比例分别存在于D2O、CD3OD-D2O和CDCl3中。因此,本发明的一个优选的实施方案是这样的组合物,其中的双环形式以双环/单环至少1∶1,优选20∶1,或甚至更大的比例至几乎全是双环化合物的形式存在;100%的双环化合物在本发明的范围内。
可根据下述通用方法制备上述式(I)双环-16-卤素化合物:
7-[(1S,3S,6S,7R)-3-庚基-3-羟基-双环[4.3.0]壬-8-酮-7-基]庚-5-烯酸异丙基酯和7-[(1S,3R,6S,7R)-3-庚基-3-羟基-双环[4.3.0]壬-8-酮-7-基]庚-5-烯酸异丙基酯的制备
1.(Z)-7-[(1R,2R,3R,5S)-2-(3,3-亚乙二氧基癸基)-5-羟基-3-(对甲苯磺酰基(sulfonyl))环戊基]庚-5-烯酸异丙基酯(2)的制备
0℃下,向二氯甲烷中的吡啶(0.77g)和(Z)-7-[(1R,2R,3R,5S)-3,5-二羟基-2-(3,3-亚乙二氧基癸基)环戊基]庚-5-烯酸异丙基酯(1)(4.05g)的混合物中加入二氯甲烷中的对甲苯磺酰氯(1.86g)溶液,并在此温度下搅拌两天。反应期间各分三批加入对甲苯磺酰氯(5.58g)和吡啶(2.31g)。常规处理后,对粗产物采用硅胶层析法,得到(Z)-7-[(1R,2R,3R,5S)-2-(3,3-亚乙二氧基癸基)-5-羟基-3-(对甲苯磺酸氧基(sulfoxy))环戊基]庚-5-烯酸异丙基酯(2)。得量3.45g,64.1%。
2.(Z)-7-[(1R,2S)-2-(3,3-亚乙二氧基癸基)-5-氧基环戊-3-烯基]庚-5-烯酸异丙基酯(3)的制备
在-40℃至-20℃用琼斯试剂在丙酮中氧化(Z)-[(1R,2R,3R,5S)-2-(3,3-亚乙二氧基癸基)-5-羟基-3-(对甲苯磺酸氧基)环戊基]庚-5-烯酸异丙基酯(2)(1.72g)4小时。常规处理后,使该粗产物通过含正己烷/乙酸乙酯(3.5/1)的硅胶垫。再经硅胶层析(正己烷/乙酸乙酯=4/1)该产物。得到(Z)-7-[(1R,2S)-2-(3,3-亚乙二氧基癸基)-5-氧基-环戊-3-烯基]庚-5-烯酸异丙基酯(3)。得量0.81g,64.6%。
3. 7-[(1R,2S,3R)-2-(3,3-亚乙二氧基癸基)-3-羟基甲基-5-氧代环戊基]庚-5-烯酸异丙基酯(4)的制备
使(Z)-7-[(1R,2S)-2-(3,3-亚乙二氧基癸基)-5-氧代-环戊-3-烯基]庚-5-烯酸异丙基酯(3)(0.81g)和二苯酮溶于甲醇中。在氩气氛围中,用300-W高压水银灯照射该溶液4小时40分钟。溶剂蒸发后,经硅胶层析(正己烷/乙酸乙酯=3/2)该粗产物,得到-7-[(1R,2S,3R)-2-(3,3-亚乙二氧基癸基)-3-羟基甲基-5-氧基环戊基]庚-5-烯酸异丙基酯(4)。得量0.41g,47%。
4. 7-[(1R,2S,3R)-2-(3,3-亚乙二氧基癸基)-5-氧代-3-(对甲苯磺酸氧基甲基)环戊基]庚-5-烯酸异丙基酯(5)的制备
使[(1R,2S,3R)-2-(3,3-亚乙二氧基癸基)-3-羟基甲基-5-氧基环戊基]庚-5-烯酸异丙基酯(4)(0.21g)和吡啶(0.07g)溶于二氧甲烷中。0℃下向该溶液中加入对甲苯磺酰氯(0.17g),并搅拌该混合物72小时。常规处理后,用硅胶层析该粗产物,得到7-(1R,2S,3R)-2-(3,3-亚乙二氧基癸基)-5-氧代-3-(对甲苯磺酸氧基)甲基环戊基]庚-5-烯酸异丙基酯(5)。得量0.25g,89%。
5. 7-[(1R,2R,3R)-2-(3,3-亚乙二氧基癸基)-3-碘甲基-5-氧基环戊基]庚-5-烯酸异丙基酯(6)的制备
使7-[(1R,2S,3R)-2-(3,3-亚乙二氧基癸基)-5-氧代-3-(对甲苯磺酸氧基)甲基环戊基]庚-5-烯酸异丙基酯(5)(0.25g)溶于丙酮,并加入碘化钠(0.12g)中。使该混合物回流3小时。向该混合物中加入碘化钠(0.097g),再使该混合物回流80分钟。常规处理后,经硅胶层析(正己烷/乙酸乙酯=5/1)该粗产物,得到7-[(1R,2R,3R)-2-(3,3-亚乙二氧基癸基)-3-碘甲基-5-氧代环戊基]庚-5-烯酸异丙基酯(6)。得到0.16g,68%。
6. 7-[(1R,2R,3R)-3-碘甲基(iodemethyl)-5-氧代-2-(3-氧代癸基)环戊基]庚-5-烯酸异丙基酯(7)的制备
使7-[(1R,2R,3R)-2-(3,3-亚乙二氧基癸基)-3-碘甲基-5-氧代环戊基]庚-5-烯酸异丙基酯(6)(0.16g)溶解于乙酸/水/四氢呋喃(3/1/1)的混合溶剂中。于室温下搅拌该混合物20小时再于50℃下搅拌2.5小时。蒸发溶剂后,经层析硅胶(正己烷/乙酸乙酯=1/1)所得的残余物,得到7-[(1R,2R,3R)-3-碘甲基-5-氧代-2-(3-氧代癸基)环戊基]庚-5-烯酸异丙基酯(7)。得量0.13g,86%。
7.异丙基7-[(1S,3S,6S,7R)-3-庚基-3-羟基-双环[4.3.0]壬-8-酮-7-基]庚-5-烯酯(8a)和7-[(1S,3R,6S,7R)-3-庚基-3-羟基-双环[4.3.0]壬-8-酮-7-基]庚-5-烯酸异丙基酯(8b)的制备
使7-[(1R,2R,3R)-3-碘甲基-2-(3-氧代癸基)-5-氧代环戊基]庚-5-烯酸异丙基酯(7)(0.0574g)和二氯化二茂锆溶解于四氢呋喃。在氩气流中超声处理该混合物以清出该混合物中的空气。向该混合物中逐滴加入四氢呋喃中的碘化钐(0.1M,2.1ml)。室温下搅拌该混合物30分钟,再加入氢氯酸(0.1M,1ml)。常规处理后,经硅胶层析(正己烷/乙酸乙酯=5/1)该粗产物。如下得到两种双环产物,多极性的(8a)及其差向异构体,少极性的(8b)和起始原料(7):
7-[(1S,3S,6S,7R)-3-庚基-3-羟基-双环[4.3.0]壬-8-酮-7-基]庚-5-烯酸异丙基酯(8a)和7-[(1S,3R,6S,7R)-3-庚基-3-羟基-双环[4.3.0]壬-8-酮-7-基]庚-5-烯酸异丙基酯(8b):得到8(a)5.1mg,得到8(b)7.2mg,回收起始原料(7)26.7mg。
其中Z为硫原子,W1为-OH基团的式(I)表示的化合物的理论合成提出如下:
n-Bu4N-F:氟化四丁基铵
DBU:1,8-二氮杂双环[5.4.0]十一碳-7-烯
DIBAL-H:氢化二异丁基铵
DMAP:4-二甲基氨基吡啶
NaBH4:硼氢化钠
下面示出其中Z为硫原子和W1为酮基的式(I)表示的化合物的理论合成:
下面示出其中Z为硫原子、W1为酮基且X1和X2为氟原子的式(I)表示的化合物的理论合成:
下面示出其中Z为氮原子的式(I)表示的化合物的理论合成:
下面示出其中Z为氮原子的式(I)表示的化合物的另一种理论合成:
本发明的制备方法不应认为是对它们的限制,还可采用适用的保护、氧化、还原等措施。
在用于本发明的双环-16-卤素化合物中,在五-元环的结构和取代基的C-16位上,当被两个卤原子,特别是氟原子独立取代,或存在双键或其它取代基时,肠蓄积活性会显著增强。特别优选的双环-16-卤素化合物是那些由在五-元环具有C-9位酮基和C-11位羟基的单环化合物形成的互变异构体。另一优选基团是含5,6-单键、5,6-双键的双环-16-卤代化合物或优选那些具有20-22个碳的双环-16-卤代化合物,其中R1优选在直链上含4-6个碳原子。
下列示出含5,6-双键的单环/双环-16-卤素化合物的一个实例:
本发明的另一实施方案包括本发明的组合物和中链脂肪酸甘油三酯。所述甘油三酯可为有6-14个碳原子、可有支链的饱和或不饱和脂肪酸。优选的脂肪酸为直链饱和脂肪酸,例如,己酸、辛酸、癸酸、月桂酸和肉豆蔻酸。可使用两种或多种中链脂肪酸甘油三酯的混合物。
通过使式(I)双环化合物溶解于或混合到中链脂肪酸甘油三酯中可制备本发明的组合物。不限定中链脂肪酸甘油三酯的量。然而,大体上说来,基于一份重量的双环结构物可使用1-1,000,000份重量的中链脂肪酸甘油三酯。优选5-500,000份重量,更优选10-200,000份重量。
用于本发明的中链脂肪酸甘油三酯的实例包括有6-14个碳原子、可有支链的饱和或不饱和脂肪酸的甘油三酯。优选的脂肪酸为直链饱和脂肪酸,例如,己酸(C6)、辛酸(C8)、癸酸(C10)、月桂酸(C12)和肉豆蔻酸(C14)。也可使用两种或多种中链脂肪酸甘油三酯的混合物。
甚至更多的非极性溶剂,例如市售可获得的Miglyol可用来增加双环/单环比例。
为举例说明本发明实施方案的制剂并说明强的位阻效应,提出一个实施例。
实施例
以列于下表中的量,使下列化合物1和2溶解于中链脂肪酸甘油三酯(MCT=辛酸甘油三酯和癸酸甘油三酯的85∶15比例的混合物)。
化合物1 化合物2
所述溶液各置于硬玻璃制成的容器中并于40℃贮藏。用HPLC方法确定溶液中化合物1和2的时间-过程含量。同时,化合物1和2各单独放置(未溶于所述溶剂中)于上述容器中,并于40℃贮藏,供对照研究。
无溶剂时,所述化合物的含量如下通过HPLC方法确定。
准确称量贮存的化合物1和2及标准化合物1和2各约0.025g,向分别称量过的化合物中准确加入5ml等份内标溶液。通过加入乙腈(液相色谱级)各得到准确总量的试验和标准制剂10mL。将试验和标准制剂各10μL装入液相色谱柱并用带一点校正曲线(one pointcalibration curve)的内标法确定所述化合物的含量。
WX:标准制剂中所述化合物的量(mg)。
WT:测试制剂中化合物1和2的量。
QS:标准制剂中的所述化合物与内标的峰值区间比率(Peak arearadio)。
QT:测试制剂中的所述化合物与内标的峰值区间比率。
测试条件:
监测器:紫外吸收分光光度计(波长294nm)
柱:装有用于液相色谱的5μm十八烷基甲硅烷基硅胶的约5mm内径和约25cm长的不锈钢管。
柱温度:稳定在约35℃
流动相:乙腈(液相色谱级)/乙酸钠水溶液(0.01mol/L)/冰醋酸的混合溶液(800∶200∶1)。
(2)有溶剂时,所述化合物的含量如下HPLC方法确定。
以示于上表中的值为基准,准确称重相当于36μg化合物1和2的所述溶液的量。准确加入1.0mL内标溶液,再加入乙酸乙酯(液相色谱级),各得到总量10mL的溶液。真空浓缩所述溶液各0.1mL至干燥,得到测试制剂。
分别准确称量18mg标准化合物并与乙酸乙酯(液相色谱级)混合,分别准确得到50mL总量。准确测量1.0mL所述溶液和10.0mL内标溶液,并与乙酸乙酯(液相色谱级)混合,各得到总量100mL。真空浓缩各0.1mL所述溶液至干燥,得到标准制剂。
向测试和标准制剂中分别加入0.1mL荧光标记试剂和0.85mL荧光标记催化剂,搅拌所述混合物并在室温下反应超过30分钟。向反应混合物中分别加入含2%乙酸的0.05mL等份乙腈(液相色谱级),搅拌,再放置超过30分钟以提供测试和标准溶液。
将各10μL测试和标准溶液分别装入液相色谱柱,并通过带一点校正曲线的内标法确定各化合物的含量。
WX:标准制剂中所述化合物的量(mg)。
QS:标准制剂中的所述化合物与内标的峰值区间比率。
QT:测试制剂中的所述化合物与内标的峰值区间比率。
测试条件:
监测器:荧光分光计(激发波长259nm;荧光波长394nm)
柱:装有用于液相色谱的5μm十八烷基甲硅烷基硅胶的约5mm内径和约25cm长的不锈钢管。
柱温度:稳定在约35℃
流动相:乙腈(液相色谱级)/甲醇(液相色谱级)/乙酸铵水溶液(0.05mol/L)的混合溶液(4∶11∶5)。
初始 | 6天 | 7天 | 14天 | 28天 | 38天 | 90天 | 191天 | ||
化合物1 | 晶体 | 100 | 97.2 | 94.1 | 87.4 | ||||
MCT1 | 100 | 101.4 | 102.1 | 100.9 | |||||
化合物2 | 晶体 | 100 | 84.5 | 75.0 | 53.4 | ||||
MCT2 | 100 | 99.6 | 98.9 | 99.6 |
1化合物1/溶剂:0.36mg/g
2化合物2/溶剂:0.12mg/g
本发明的组合物产生极大的肠蓄积作用,抑制肠内水的吸收。而且,本发明的化合物没有或如有的话也大大减少了PGEs或PGFs引起的肠的收缩作用。因此,本发明的化合物治疗便秘无肠收缩引起的腹部不适例如腹痛。而且,所述化合物使便秘对正常肠状况的影响减弱。此外,对肠内的转运有极大促进作用的本发明化合物如果引起腹泻症状,很快即可恢复。因此,作为泻药它们是非常有用的。
本发明的组合物可用作动物或人体便秘的治疗和预防药物,并一般通过口服给药或作为栓剂、灌肠剂等用于全身或局部应用。有时它们可用作静脉或皮下注射剂。其剂量随动物、人体、年龄、体重、症状、疗效、给药途径、治疗时间等而不同。优选地,剂量为0.001-1,000μg/kg,更优选0.01-100μg/kg。
本发明的组合物也可用来提供一种肠清洗剂,用于预防、诊断或外科手术例如内镜检查、结肠镜检查、双对比(double-contrast)钡灌肠x-射线造影剂和静脉肾盂造影术之前的肠预处理,和用于紧急程序例如解除药物或食物中毒。
本发明的口服固体组合物包括片剂、制剂、颗粒剂等。在这样的固体组合物中,一种或多种活性成分可与至少一种非活性稀释剂例如乳糖、甘露糖醇、葡萄糖、羟丙基纤维素、微晶纤维素、淀粉、聚乙烯吡咯烷酮、铝酸镁硅酸盐(magnesium aluminate metasilicate)等混合。根据通常的加工方法,所述组合物可含有除非活性稀释剂外的其它添加剂,例如,润滑剂例如硬脂酸镁;崩解剂例如纤维状葡萄糖酸钙;稳定剂例如环糊精例如,α,β-或γ-环糊精;醚化环糊精例如二甲基-α-、二甲基-β-、三甲基-β-或羟丙基-β-环糊精;支链环糊精例如葡糖基-、麦芽糖基-环糊精;甲酰化环糊精、含硫环糊精;磷脂等。当采用上述环糊精时,有时形成与环糊精的包含化合物以增加稳定性。另外,有时可用磷酯来形成脂质体,导致稳定性提高。
需要时,可用可溶解于胃或肠中的薄膜例如蔗糖、明胶、羟丙基纤维素、羟丙基甲基纤维素邻苯二甲酸酯对片剂或丸剂包衣。而且,它们可用可吸收物质例如明胶形成胶囊。
口服给药的液体组合物可含药学上可接受的乳化剂、溶液、悬液、糖浆剂、酏剂及常用的非活性稀释剂。除所述非活性稀释剂外,这类组合物可含辅剂例如悬浮剂、增甜剂、增香剂、防腐剂、增溶剂、抗氧化剂等。所述添加剂的详情可从药学领域任何普通教科书所描述的那些添加剂中选择。这类液体组合物可直接包含在软胶囊中。然而,必须小心选择所述双环/单环化合物会溶解或混合于其中的、不同于上述的稀释剂,以使不致影响双环/单环的比例。
根据本发明的不经肠给药的溶液,例如,栓剂、灌肠剂等包括无菌的含水或不含水溶液、悬液、乳液等。含水溶液和悬液包括,例如,蒸馏水、生理盐水和林格氏溶液。
所述的不含水溶液和悬液包括,例如,丙二醇、聚乙二醇、脂肪酸甘油三酯、植物油例如橄榄油、醇例如乙醇、聚山梨醇酯等。这类组合物可含辅剂例如防腐剂、增湿剂、乳化剂、分散剂、抗氧化剂等。
以下实施例将说明本发明。只是通过实施例来说明并非要限制本发明的范围。
单环/双环结构和生物学活性的相关性
为举例说明本发明组合物中在C-16位具有卤原子的卤代双环化合物的功效,制备并测试以下实施例。
实施例1
当通式(I)中的Z为氧原子、酮基在本发明的C-9位时,归因于单环/双环结构比例的组合物的生物学活性可从下列实施例中看出。C-16位的氟原子数目和单环/双环结构的比例见表1。
进行肠蓄积测试和腹泻测试。其结果列于表1中。肠内含量提高50%的剂量表示为ED50。
表1
实施例A | 实施例B | 比例实施例A | |
在C-16位的F原子数 | 2 | 1 | 0 |
单环/双环结构的比例* | 4∶96 | 1∶1 | 未测到双环结构产生的信号 |
肠蓄积活性,ED50 | 0.6μg/kg | 2μg/kg | 320μg/kg |
小鼠腹泻 | +:在3mg/kg(PO1)+:在0.3mg/kg(SC2) | ±:在0.3mg/kg(SC) | -:在10mg/kg(PO)-:在1mg/kg(SC) |
*在CDCl3溶液中的NMR测定法检测。
1PO指经口(口服给药)
2SC指皮下给药
实施例2
当式(I)中的Z为氧原子、酮基在C-9位并在5,6-碳原子之间有一个双键时,归因于单环/双环结构比例的所述组合物的生物学活性表示如下。
进行肠蓄积测试和腹泻测试。其结果列于表2中。肠内含量提高50%的剂量表示为ED50。
表2
实施例C | 实施例D | 比例实施例C | |
在C-16位的F原子数 | 2 | 1 | 0 |
单环/双环结构的比例* | 4∶96 | 1∶1 | 未测到双环结构产生的信号 |
肠蓄积活性,ED50 | 0.3μg/kg | 3μg/kg | 220μg/kg |
小鼠腹泻 | +:在1mg/kg(PO)1 | -:在1mg/kg(PO)+:在5mg/kg(PO) | -:在10mg/kg(PO) |
*经CDCl3溶液中的NMR测定法检测。
1PO指经口(口服给药)
健康男性志愿者单次口服给药后溶解于中链脂肪酸甘油三酯的本发明组合物对肠运动的作用
用含4∶96比例的下列单环/双环结构(在CDCl3中)的组合物向3-9名健康男性志愿者给药。
使测试物质R1和R2为F原子)溶解于Panacet 800(由日本Amagasaki的Nippon Oil & Fat co.,Ltd.,生产的中链脂肪酸甘油三酯)并装入胶囊(每个胶囊含200L所述混合物)。每位患者用100mL水服用一个胶囊。
表3表示排出稀便或腹泻的患者数。
表3
剂量 | 人数 | |
正常 | 稀便或腹泻 | |
5μg | 1/3 | 2/3 |
10μg | 5/7 | 2/7 |
20μg | 1/3 | 2/3 |
30μg | 2/9 | 7/9 |
尽管已详细并参考其具体实施方案描述本发明,但在不背离其精神和范围的情况下可进行各种改变和修饰,这对本领域的技术人员而言是显而易见的。
Claims (42)
1.一种泻药组合物,它包括一种导泻有效量的由式(I)表示的双环化合物:
其中V1和V2为碳或氧;
W1在V1为碳和W2在V2为碳时是
R3和R4为氢或其中之一为OH;
X1和X2为氢、低级烷基或卤素,且其中至少一个为卤素;
Z为碳、氧、硫或氮;
R2为氢或烷基;
Y为饱和或不饱和C2-10烃链,它未被取代或被氧代、卤素、烷基、羟基、芳基或杂环基取代;
A为-CH2OH、-COCH2OH、-COOH或它的官能团衍生物;和
R1为饱和或不饱和的,成直链或支链的低级烃,它是未被取代的或被卤素、氧代、羟基、低级烷氧基、低级烷酰氧基、低级环烷基、低级环烷氧基、芳基、芳氧基、杂环基或杂环氧基取代;低级环烷基;低级环烷氧基;芳基、芳氧基、杂环基或杂环氧基;
C-13和C-14位之间的键为双键或单键,和
C-15有R、S的空间构型或其混合物。
2.权利要求1的组合物,它还包括产生双环对单环结构之比例至少为1∶1的量的式(I)单环互变异构体的化合物。
3.权利要求1的组合物,它还包括产生双环对单环结构之比例至少为20∶1的量的式(I)单环互变异构体的化合物。
4.权利要求1的组合物,其中A为-COOH,W1为酮,Z为氧原子,R2为氢原子,且X1和X2是氟原子。
5.权利要求1的组合物,其中Z为硫原子或氮原子。
6.权利要求1的组合物,其中A为COOH;Y为(CH2)6;W1为=O;R3和R4为氢原子;V1和V2为碳原子;Z为氧原子,X1和X2是氟原子;而R1为(CH2)3CH3。
7.权利要求1-6任一项的组合物,它进一步包括中链脂肪酸甘油三酯。
8.权利要求7的组合物,其中的中链脂肪酸甘油三酯以基于一份重量的式(I)双环化合物的1-1,000,000份重量的量存在。
9.权利要求8的组合物,其中的中链脂肪酸甘油三酯以基于一份重量的式(I)双环化合物的5-500,000份重量的量存在。
10.权利要求9的组合物,其中的中链脂肪酸甘油三酯以基于一份重量的式(I)双环化合物的10-200,000份重量的量存在。
11.权利要求7的组合物,其中的中链脂肪酸甘油三酯为有6-14个碳原子的脂肪酸的甘油三酯。
12.权利要求11的组合物,其中的中链脂肪酸甘油三酯为辛酸甘油三酯和/或癸酸甘油三酯。
13.权利要求1-12的任一项的组合物,它用于缓解或预防便秘病人的便秘。
14.权利要求1-12的任一项的组合物,它用于清洗肠道。
15.一种对有此需要的患者提供导泻作用的方法,它包括给予患者含导泻有效量的式(I)双环化合物的组合物。
其中V1和V2为碳或氧;
W1在V1为碳和W2在V2为碳时是
R3和R4为氢或其中之一为OH;
X1和X2为氢、低级烷基或卤素,且其中至少之一为卤素;
Z为碳、氧、硫或氮;
R2为氢或烷基;
Y为饱和或不饱和C2-10烃链,它未被取代或被氧代、卤素、烷基、羟基、芳基或杂环基取代;
A为-CH2OH、-COCH2OH、-COOH或它的官能团衍生物;和
R1为饱和或不饱和的、成直链或支链的低级烃,它为未被取代的或被卤素、氧代、羟基、低级烷氧基、低级烷酰氧基、低级环烷基、低级环烷氧基、芳基、芳氧基、杂环基或杂环氧基取代;低级环烷基;低级环烷氧基;芳基、芳氧基、杂环基或杂环氧基;
C-13和C-14位之间的键为双键或单键,和
C-15有R、S的空间构型或其混合物。
16.权利要求15的方法,其中的组合物还包括一定量的式(I)双环化合物的单环互变异构体的、使双环与单环结构之比至少为1∶1的化合物。
17.权利要求16的方法,其中的双环与单环结构之比例至少为20∶1。
18.权利要求15的方法,其中A为-COOH,W1为酮,Z为氧原子,R2为氢原子,和X1和X2是氟原子。
19.权利要求15的方法,其中Z为硫原子或氮原子。
20.根据权利要求15的方法,其中A为COOH;Y为(CH2)6;W1为=O;R3和R4为氢原子;V1和V2为碳原子;Z为氧原子,X1和X2是氟原子;而R1为(CH2)3CH3。
21.权利要求15-20任一项的方法,其中的组合物还包括中链脂肪酸甘油三酯。
22.权利要求21的方法,其中的中链脂肪酸甘油三酯以基于一份重量的式(I)双环化合物的1-1,000,000份重量的量存在。
23.权利要求22的方法,其中的中链脂肪酸甘油三酯以基于一份重量的式(I)双环化合物的5-500,000份重量的量存在。
24.权利要求23的方法,其中的中链脂肪酸甘油三酯以基于一份重量的式(I)双环化合物的10-200,000份重量的量存在。
25.权利要求21的方法,其中的中链脂肪酸甘油三酯为具有6-14个碳原子的脂肪酸的甘油三酯。
26.权利要求25的方法,其中的中链脂肪酸甘油三酯为辛酸甘油三酯和/或癸酸甘油三酯。
27.权利要求15-26的任一项的方法,该方法用于缓解或预防病人的便秘。
28.权利要求15-26的任一项的方法,该方法用于清洗肠道。
29.式(I)双环化合物在制备泻药组合物中的用途:
其中V1和V2为碳或氧;
W1在V1为碳和W2在V2为碳时是
R3和R4为氢或其中之一为OH;
X1和X2为氢、低级烷基或卤素,且其中至少一个为卤素;
Z为碳、氧、硫或氮;
R2为氢或烷基;
Y为饱和或不饱和C2-10烃链,它为未被取代的或被氧代、卤素、烷基、羟基、芳基或杂环基取代;
A为-CH2OH、-COCH2OH、-COOH或它的官能团衍生物;和
R1为饱和或不饱和的、成直链或支链的低级烃,它为未被取代的或被卤素、氧代、羟基、低级烷氧基、低级烷酰氧基、低级环烷基、低级环烷氧基、芳基、芳氧基、杂环基或杂环氧基取代;低级环烷基;低级环烷氧基;芳基、芳氧基、杂环基或杂环氧基;
C-13和C-14位之间的键为双键或单键,和
C-15有R、S的空间构型或其混合物。
30.权利要求29的用途,其中的组合物还包括一定量的式(I)双环化合物的单环互变异构体的、使双环与单环结构之比例至少为1∶1的化合物。
31.权利要求30的用途,其中的双环与单环结构之比例至少为20∶1。
32.权利要求29的用途,其中A为-COOH,W1为酮,Z为氧原子,R2为氢原子,X1和X2是氟原子。
33.权利要求29的用途,其中Z为硫原子或氮原子。
34.权利要求29的用途,其中A为COOH;Y为(CH2)6;W1为=O;R3和R4为氢原子;V1和V2为碳原子;Z为氧原子,X1和X2是氟原子;而R1为(CH2)3CH3。
35.权利要求29-34之任一项的用途,其中的组合物还包括中链脂肪酸甘油三酯。
36.权利要求35的用途,其中的中链脂肪酸甘油三酯以基于一份重量的式(I)双环化合物的1-1,000,000份重量的量存在。
37.权利要求36的用途,其中的中链脂肪酸甘油三酯以基于一份重量的式(I)双环化合物的5-500,000份重量的量存在。
38.权利要求37的用途,其中的中链脂肪酸甘油三酯以基于一份重量的式(I)双环化合物的10-200,000份重量的量存在。
39.权利要求35的用途,其中的中链脂肪酸甘油三酯为具有6-14个碳原子的脂肪酸的甘油三酯。
40.权利要求39的用途,其中的中链脂肪酸甘油三酯为辛酸甘油三酯和/或癸酸甘油三酯。
41.权利要求29-40的任一项的用途,该用途为缓解或预防病人的便秘。
42.权利要求29-40的任一项的用途,该用途为清洗肠道。
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/655,760 | 2000-09-05 | ||
US09/655,760 US6414016B1 (en) | 2000-09-05 | 2000-09-05 | Anti-constipation composition |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1655776A true CN1655776A (zh) | 2005-08-17 |
CN100335049C CN100335049C (zh) | 2007-09-05 |
Family
ID=24630250
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CNB018183239A Ceased CN100335049C (zh) | 2000-09-05 | 2001-09-04 | 泻药组合物 |
Country Status (25)
Country | Link |
---|---|
US (7) | US6414016B1 (zh) |
EP (2) | EP1857105B1 (zh) |
JP (3) | JP2004508327A (zh) |
KR (2) | KR100901102B1 (zh) |
CN (1) | CN100335049C (zh) |
AR (2) | AR030609A1 (zh) |
AT (1) | ATE476975T1 (zh) |
AU (2) | AU8261501A (zh) |
BR (1) | BRPI0114042B8 (zh) |
CA (1) | CA2419741C (zh) |
CZ (1) | CZ304740B6 (zh) |
DE (2) | DE60131547T2 (zh) |
DK (2) | DK1857105T3 (zh) |
ES (2) | ES2296786T3 (zh) |
HU (1) | HU229319B1 (zh) |
IL (2) | IL154534A0 (zh) |
MX (1) | MXPA03001959A (zh) |
NL (1) | NL300757I1 (zh) |
NO (1) | NO332701B1 (zh) |
NZ (1) | NZ524401A (zh) |
PT (2) | PT1315485E (zh) |
RU (1) | RU2694361C3 (zh) |
TW (1) | TWI305147B (zh) |
WO (1) | WO2002020007A1 (zh) |
ZA (1) | ZA200301673B (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101318948B (zh) * | 2008-04-01 | 2011-04-27 | 上海天伟生物制药有限公司 | 鲁比前列酮晶体、其制备方法及用途 |
Families Citing this family (44)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DK1426361T4 (en) * | 1999-10-15 | 2015-03-16 | Sucampo Ag | Novel compounds containing a bi-cyclic compound and a glyceride |
US6414016B1 (en) * | 2000-09-05 | 2002-07-02 | Sucampo, A.G. | Anti-constipation composition |
TWI302100B (en) * | 2001-05-02 | 2008-10-21 | Sucampo Ag | Composition for treating drug-induced constipation |
AR037524A1 (es) | 2001-11-14 | 2004-11-17 | Sucampo Ag | Unidad de dosificacion que comprende un analogo de prostaglandina para el tratamiento de la constipacion |
TWI263505B (en) * | 2001-11-19 | 2006-10-11 | Sucampo Ag | Pharmaceutical composition comprising a C1C-2 channel opener |
WO2004037268A1 (en) * | 2002-10-23 | 2004-05-06 | Sucampo Ag | Prostaglandin compounds for the treatment of obesity |
EP1575596B1 (en) * | 2002-12-27 | 2016-06-22 | Sucampo AG | Derivatives of prostaglandins for treating irritable bowel syndrome and/or functional dyspepsia |
US8337891B2 (en) | 2003-07-03 | 2012-12-25 | Sucampo Ag | Enteric coated composition comprising prostaglandin analogs as chloride channel opener |
TWI495471B (zh) * | 2003-08-12 | 2015-08-11 | R Tech Ueno Ltd | 促進毛髮生長之組成物及方法 |
TWI387454B (zh) * | 2004-09-02 | 2013-03-01 | Sucampo Ag | 治療胃腸道疾病之方法及組成物 |
KR101354771B1 (ko) | 2005-01-27 | 2014-01-22 | 수캄포 아게 | 중추 신경계 질환 치료를 위한 방법 및 조성물 |
TW201410248A (zh) * | 2005-03-04 | 2014-03-16 | Sucampo Ag | 處理週邊血管疾患之方法及組成物 |
US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
CA2600350C (en) * | 2005-03-07 | 2015-02-10 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
US20060281818A1 (en) | 2005-03-21 | 2006-12-14 | Sucampo Ag, North Carolina State University | Method for treating mucosal disorders |
WO2006109881A1 (en) * | 2005-04-12 | 2006-10-19 | Sucampo Ag | Combined use of prostaglandin compound and proton pump inhibitor for the treatment of gastrointestinal disorders |
RU2440144C2 (ru) * | 2006-01-24 | 2012-01-20 | Р-Тек Уено, Лтд. | Фармацевтическая композиция, содержащая бициклическое соединение, и способ стабилизации бициклического соединения |
HUE034571T2 (en) * | 2006-02-07 | 2018-02-28 | Sucampo Pharma Llc | A method for preparing a prostaglandin derivative |
US20090012165A1 (en) * | 2007-07-03 | 2009-01-08 | Sucampo Ag | Pharmaceutical combination of nsaid and prostaglandin compound |
US20090030072A1 (en) | 2007-07-03 | 2009-01-29 | Sucampo Ag | Pharmaceutical combination of opioid and prostaglandin compound |
US20090082442A1 (en) * | 2007-09-26 | 2009-03-26 | Protia, Llc | Deuterium-enriched lubiprostone |
US8513441B2 (en) * | 2008-08-29 | 2013-08-20 | Alphora Research Inc. | Prostaglandin synthesis and intermediates for use therein |
DK2349250T3 (en) * | 2008-10-31 | 2017-07-03 | Lipid Pharmaceuticals Ehf | Fatty acids for use as a medicament |
HUE036405T2 (hu) | 2008-12-31 | 2018-07-30 | Ardelyx Inc | Vegyületek és módszerek az NHE-közvetített (Na+/H+ cserével mûködõ) antiport gátlására folyadékretencióval vagy túlzott sómennyiség jelenlétével és a gyomor-bél traktus zavaraival összefüggõ rendellenességek kezelésében |
WO2018129556A1 (en) | 2017-01-09 | 2018-07-12 | Ardelyx, Inc. | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
EP2429982A4 (en) | 2009-01-22 | 2012-09-12 | Apotex Pharmachem Inc | METHOD FOR THE PRODUCTION OF LUBIPROSTON AND INTERMEDIATE PRODUCTS THEREOF |
US9084815B2 (en) * | 2009-09-16 | 2015-07-21 | Sucampo Ag | Method for treating damage induced by an anti-tumor agent, treating mucositis and treating tumor |
PE20120991A1 (es) * | 2009-09-18 | 2012-08-01 | Adolor Corp | Antagonista del receptor opiaceo para los trastornos del tracto gastrointestinal |
US8940790B2 (en) * | 2009-11-03 | 2015-01-27 | Bernard Charles Sherman | Stable pharmaceutical formulations comprising lubiprostone |
US20120309990A1 (en) * | 2009-12-18 | 2012-12-06 | Apotex Pharmachem Inc. | Processes for the Purification of Lubiprostone |
CA2788334A1 (en) | 2010-01-28 | 2011-08-04 | Apotex Pharmachem Inc. | Polymorphic forms of lubiprostone |
CA2880338A1 (en) | 2012-08-21 | 2014-02-27 | Ardelyx, Inc. | Compounds and methods for inhibiting nhe-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
US10376481B2 (en) | 2012-08-21 | 2019-08-13 | Ardelyx, Inc. | Compounds and methods for inhibiting NHE-mediated antiport in the treatment of disorders associated with fluid retention or salt overload and gastrointestinal tract disorders |
WO2014159679A1 (en) | 2013-03-12 | 2014-10-02 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Methods for using lubiprostone to absorb fluid from the subretinal space |
SI2983667T1 (sl) | 2013-04-12 | 2019-09-30 | Ardelyx, Inc. | Spojine za vezavo NHE3 in metode za zaviranje transporta fosfata |
EP3277274A4 (en) | 2015-04-01 | 2018-12-05 | Cedars-Sinai Medical Center | Anti-methanogenic lovastatin analogs or derivatives and uses thereof |
US20170020890A1 (en) * | 2015-06-19 | 2017-01-26 | Sucampo Ag | Pharmaceutical composition comprising fatty acid derivative |
WO2018065826A1 (en) | 2016-10-06 | 2018-04-12 | Sucampo Ag | Multilayer beads for pharmaceutical use |
US11147884B2 (en) | 2017-01-09 | 2021-10-19 | Ardelyx, Inc. | Inhibitors of NHE-mediated antiport |
EP3565808A1 (en) | 2017-01-09 | 2019-11-13 | Ardelyx, Inc. | Compounds useful for treating gastrointestinal tract disorders |
JP6750733B2 (ja) * | 2017-04-20 | 2020-09-02 | 株式会社島津製作所 | 分光光度計 |
US10422729B1 (en) | 2019-03-08 | 2019-09-24 | Biodesix, Inc. | Blood sample separation devices and methods |
Family Cites Families (27)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS5720305B2 (zh) | 1973-02-28 | 1982-04-27 | ||
US4034003A (en) | 1974-04-11 | 1977-07-05 | Ono Pharmaceutical Co., Ltd. | 15-Cycloalkyl-prostaglandins |
JPS5350141A (en) | 1976-10-18 | 1978-05-08 | Ono Pharmaceut Co Ltd | Stabilization of prostaglandin and prostaglandin analogues |
JPS5391110A (en) | 1977-01-20 | 1978-08-10 | Yamanouchi Pharmaceut Co Ltd | Novel drug composition for rectal infusion |
JPS6022708B2 (ja) | 1977-07-14 | 1985-06-03 | 小野薬品工業株式会社 | プロスタグランジン類似化合物 |
US4308595A (en) * | 1979-12-19 | 1981-12-29 | International Business Machines Corporation | Array driver |
US4670569A (en) | 1981-04-02 | 1987-06-02 | G. D. Searle & Co. | 5-fluoro-PGI2 compounds |
US4687864A (en) | 1983-12-23 | 1987-08-18 | G. D. Searle & Co. | 5-fluoro-3-oxa-prostacyclin compounds |
US4579958A (en) | 1983-12-23 | 1986-04-01 | G. D. Searle & Co. | 5-fluoro-3-oxa-6,7-didehydro-PGI1 compounds |
US5166174A (en) * | 1987-01-28 | 1992-11-24 | K.K. Ueno Seiyaku Oyo Kenkyujo | Prostaglandins E and anti-ulcers containing same |
JPH0681728B2 (ja) * | 1987-10-02 | 1994-10-19 | 株式会社上野製薬応用研究所 | 下 剤 |
US5317032A (en) | 1987-10-02 | 1994-05-31 | Kabushiki Kaisha Ueno Seiyaku Oyo Kenkyujo | Prostaglandin cathartic |
ES2051862T3 (es) | 1987-10-02 | 1994-07-01 | Ueno Seiyaku Oyo Kenkyujo Kk | Un metodo para producir un medicamento que tiene un efecto catartico. |
JP2579193B2 (ja) | 1988-07-19 | 1997-02-05 | 小野薬品工業株式会社 | 16,16−ジフルオロ−15−オキソ−15−デオキシpge誘導体 |
CA2030345C (en) | 1989-11-22 | 1998-12-08 | Ryuji Ueno | Use of 15-keto-prostaglandin compound for improvement of encephalic function |
CA2030346C (en) * | 1989-11-22 | 2000-04-11 | Ryuji Ueno | Treatment of cardiac dysfunction with 15-keto-prostaglandin compounds |
ATE174221T1 (de) * | 1990-05-01 | 1998-12-15 | R Tech Ueno Ltd | Behandlung von pankreaskrankheit mit 15-keto- prostaglandin e-derivaten |
JP2515442B2 (ja) * | 1990-05-01 | 1996-07-10 | 株式会社上野製薬応用研究所 | 膵臓疾患処置剤 |
JP2938579B2 (ja) | 1990-12-15 | 1999-08-23 | 株式会社上野製薬応用研究所 | 消化管壁保護剤 |
CA2150287C (en) | 1994-06-03 | 2004-08-10 | Ryuji Ueno | Agent for treating hepato-biliary diseases |
US5958876A (en) * | 1996-06-19 | 1999-09-28 | Novartis Ag | Cyclosporin-containing pharmaceutical compositions |
AUPO665397A0 (en) * | 1997-05-07 | 1997-05-29 | Borody, Thomas Julius | Novel therapy for constipation |
DK1062952T3 (da) * | 1998-03-11 | 2003-11-24 | Grelan Pharmaceutical Co | Brusende enteropræparater |
US6471085B1 (en) | 1999-10-04 | 2002-10-29 | Anthony J. Gallo | Temperature cup |
DK1426361T4 (en) * | 1999-10-15 | 2015-03-16 | Sucampo Ag | Novel compounds containing a bi-cyclic compound and a glyceride |
ES2252286T3 (es) * | 2000-07-14 | 2006-05-16 | Henkel Kommanditgesellschaft Auf Aktien | Cuerpos huecos con compartimentos, que contienen una porcion de detergente textil, de limpieza lavavajillas. |
US6414016B1 (en) * | 2000-09-05 | 2002-07-02 | Sucampo, A.G. | Anti-constipation composition |
-
2000
- 2000-09-05 US US09/655,760 patent/US6414016B1/en not_active Expired - Lifetime
-
2001
- 2001-09-04 KR KR1020037003261A patent/KR100901102B1/ko active Protection Beyond IP Right Term
- 2001-09-04 AU AU8261501A patent/AU8261501A/xx active Pending
- 2001-09-04 RU RU2003109622A patent/RU2694361C3/ru active Protection Beyond IP Right Term
- 2001-09-04 DE DE60131547T patent/DE60131547T2/de not_active Expired - Lifetime
- 2001-09-04 AT AT07016834T patent/ATE476975T1/de active
- 2001-09-04 IL IL15453401A patent/IL154534A0/xx unknown
- 2001-09-04 ES ES01961333T patent/ES2296786T3/es not_active Expired - Lifetime
- 2001-09-04 CZ CZ2003-787A patent/CZ304740B6/cs not_active IP Right Cessation
- 2001-09-04 CN CNB018183239A patent/CN100335049C/zh not_active Ceased
- 2001-09-04 NZ NZ524401A patent/NZ524401A/en not_active IP Right Cessation
- 2001-09-04 ES ES07016834T patent/ES2347697T3/es not_active Expired - Lifetime
- 2001-09-04 TW TW090121835A patent/TWI305147B/zh not_active IP Right Cessation
- 2001-09-04 BR BRPI0114042A patent/BRPI0114042B8/pt not_active IP Right Cessation
- 2001-09-04 DK DK07016834.9T patent/DK1857105T3/da active
- 2001-09-04 WO PCT/JP2001/007628 patent/WO2002020007A1/en active IP Right Grant
- 2001-09-04 KR KR1020087021218A patent/KR100918223B1/ko active Protection Beyond IP Right Term
- 2001-09-04 DE DE60142810T patent/DE60142810D1/de not_active Expired - Lifetime
- 2001-09-04 DK DK01961333T patent/DK1315485T3/da active
- 2001-09-04 JP JP2002524492A patent/JP2004508327A/ja active Pending
- 2001-09-04 MX MXPA03001959A patent/MXPA03001959A/es active IP Right Grant
- 2001-09-04 EP EP07016834A patent/EP1857105B1/en not_active Expired - Lifetime
- 2001-09-04 PT PT01961333T patent/PT1315485E/pt unknown
- 2001-09-04 PT PT07016834T patent/PT1857105E/pt unknown
- 2001-09-04 AU AU2001282615A patent/AU2001282615B2/en not_active Expired
- 2001-09-04 CA CA2419741A patent/CA2419741C/en not_active Expired - Lifetime
- 2001-09-04 EP EP01961333A patent/EP1315485B1/en not_active Expired - Lifetime
- 2001-09-04 HU HU0302422A patent/HU229319B1/hu unknown
- 2001-09-05 AR ARP010104216A patent/AR030609A1/es unknown
-
2002
- 2002-05-06 US US10/138,650 patent/US6610732B2/en not_active Expired - Fee Related
-
2003
- 2003-02-19 IL IL154534A patent/IL154534A/en not_active IP Right Cessation
- 2003-02-28 ZA ZA200301673A patent/ZA200301673B/xx unknown
- 2003-03-04 NO NO20030996A patent/NO332701B1/no not_active IP Right Cessation
- 2003-05-22 US US10/443,046 patent/US20030216465A1/en not_active Abandoned
-
2005
- 2005-06-02 US US11/142,251 patent/US8071613B2/en not_active Expired - Fee Related
-
2009
- 2009-03-04 JP JP2009050902A patent/JP4684334B2/ja not_active Expired - Fee Related
- 2009-09-15 JP JP2009213058A patent/JP2009286806A/ja active Pending
-
2011
- 2011-10-17 US US13/274,612 patent/US8114890B1/en not_active Expired - Lifetime
- 2011-12-27 US US13/337,488 patent/US8748454B2/en not_active Expired - Fee Related
-
2013
- 2013-08-26 AR ARP130103006A patent/AR100291A2/es not_active Application Discontinuation
-
2014
- 2014-04-30 US US14/265,467 patent/US20140235665A1/en not_active Abandoned
-
2015
- 2015-08-28 NL NL300757C patent/NL300757I1/nl unknown
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101318948B (zh) * | 2008-04-01 | 2011-04-27 | 上海天伟生物制药有限公司 | 鲁比前列酮晶体、其制备方法及用途 |
US8748482B2 (en) | 2008-04-01 | 2014-06-10 | Shanghai Techwell Biopharmaceutical Co., Ltd | Lubiprostone crystal, the use and the method for the preparation thereof |
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN100335049C (zh) | 泻药组合物 | |
CN1522147A (zh) | 含有15-酮基-前列腺素类化合物的用于治疗药物诱导的便秘的组合物 | |
AU2001282615A1 (en) | Cathartic composition | |
US20050261375A1 (en) | Method for providing a cathartic effect | |
CN1043713A (zh) | 新的治疗活性化合物及其制备方法 | |
US8202909B2 (en) | Method for treating central nervous system disorders | |
CN1106844C (zh) | 前列腺烷酸化合物治疗视神经障碍 | |
TW209170B (zh) | ||
CN1206997C (zh) | 内皮缩血管肽拮抗剂 | |
CN1753680A (zh) | 用于治疗腹部不适的前列腺素衍生物 | |
CN1028233C (zh) | 具有抑制胃酸作用的取代的苯并咪唑的制备方法 | |
CN1241570C (zh) | 胆汁分泌促进组合物 | |
CN1031827C (zh) | 取代的苯并咪唑的制备方法 | |
CN1544425A (zh) | 瑞香素衍生物 | |
US5234954A (en) | Treatment of hyperlipidemia with 15-keto-prostaglandin compounds | |
CN101048163A (zh) | 用于治疗胃肠道疾病的前列腺素衍生物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
IW01 | Full invalidation of patent right | ||
IW01 | Full invalidation of patent right |
Decision date of declaring invalidation: 20181228 Decision number of declaring invalidation: 38426 Granted publication date: 20070905 |